Tuberculosis is the leading cause of infectious deaths worldwide. Inability to detect infection before overt disease has limited our understanding of early infectious processes. Our goal is to explore and characterize early events in tuberculosis in experimentally-infected guinea pigs and tuberculosis patients. We will use newly available, highly sensitive technology to understand these biological processes, based on evidence we have collected that Mycobacterium tuberculosis DNA and RNA can be detected in peripheral blood mononuclear cells (PBMCs). DNA and RNA will be extracted from PBMCs of experimentally infected guinea pigs and patients with tuberculosis, and subjected to real-time, quantitative PCR (qPCR) to estimate the number of MTB genomes. We will then measure several bacterial transcripts using reverse-transcriptase qPCR, to determine MTB viability and the association between gene expression profiles and active or latent states. We will also explore if there is a differential expression of MTB DNA and RNA depending on the host blood cell type. These assays will be used to determine biological profiles in patients with different stages of tuberculosis, based on clinical and microbiological findings. These studies should provide highly sensitive, specific and non-invasive tools to study host-pathogen events in early tuberculosis. We anticipate that the development of these tools will provide a strategy for early disease screening and prediction of progression, leading to improved tuberculosis control.